In a world-first, scientists have grown functional sections of oesophagus using stem cells and transplanted them into mice. Although early-stage, the findings, published in Nature Communications, offer a potential path towards developing treatments for children with oesophageal defects in the future.
The study, led by researchers at the Francis Crick Institute, UCL Great Ormond Street Institute of Child Health (ICH) and Great Ormond Street Hospital (GOSH) is the first of its kind for a complex multi-layered organ, overcoming a major challenge of regenerative medicine: different early-stage cells need different conditions to develop into the right cell type.
“We were amazed to see that our engineered tissue had both the structure and function of a healthy oesophagus, and hooked up with nearby blood vessels within a week of transplantation – a promising step forward in our pursuit to create better treatments for patients with oesophageal defects,” says Paola Bonfanti, joint-senior author of the paper, group leader at the Crick and Principal Research Associate at ICH.
In this proof-of-concept study, the team engineered pieces of oesophagus – approximately 2cm in length – by injecting different stem cells into rat tissue scaffolds, in stages, under the optimum conditions for each cell type.
First, they injected early-stage connective tissue and muscle cells from mice and humans into the scaffold, which formed muscle layers when the scaffold was made to mimic the movements of an oesophagus. Next, they injected mouse early-nerve cells, which formed neurons that innervated the muscle layers. Finally, they injected rat early-epithelial cells which formed a functional cell barrier lining the inside of the oesophagus. They used stem cells from different species so that they could check which tissues were derived from which cells.
“To our surprise, in a relatively short amount of time, the stem cells we injected on the oesophagus scaffold matured into fully functional cells,” says Luca Urbani, first-author of the paper.
When complete, the mini oesophagi had all the right layers of different cell types, were capable of muscle contraction – needed to move food down to the stomach – and could be preserved at low temperatures. This opens up the possibility of mass-producing and storing them ready for transplantation, if this approach were to be scaled-up for patients in the clinic.
When the team transplanted the oesophagi into a fatty sheet of tissue in the mouse abdomen, known as the omentum, they formed a functional blood supply, crucial for cell survival. The omentum was chosen as the site of transplantation because it is easier to operate on the abdomen of small animals, like mice, than the upper chest. The omentum also has a rich blood supply which helps transplanted organs survive.
Paolo De Coppi, co-senior author of the paper, consultant at GOSH and head of Stem Cells and Regenerative Medicine at ICH says: “This is a major step forward for regenerative medicine, bringing us ever closer to treatment that goes beyond repairing damaged tissue and offers the possibility of rejection-free organs and tissues for transplant. At GOSH we see referrals for some of the most complex and rare defects of the gut, such as oesophageal atresia, and though the outlook for children who have it is good, the condition and treatments have long-term implications.”
“We’re really excited about these promising preclinical findings,” says Paolo. However, lots more research lies ahead before we can safely and effectively translate this approach to humans.”
Next steps will include scaling the study up to pigs to see if the approach works in larger animals –where they hope to transplant the oesophagi into the chest – and continuing fundamental research on the different cell types that make up a functional oesophagus.
The study was funded by the UK Stem Cell Foundation, the Cell and Gene Therapy Catapult, the Great Ormond Street Hospital Charity and the OAK Foundation. Additional support was provided by the Rosetrees Trust. The National Institute for Health Research GOSH Biomedical Research Centre supported the work using human cells.